Concentrated levels of polyoxyalkylene block copolymers are useful in vehicles incorporated into products that are designed to deliver compositions, materials and substances to moistened surfaces and aqueous environment. Acquiring moisture during use, the vehicle becomes sufficiently transformed from a liquid to a gel-like form that provides a benefit to the user. For example, mucosal surfaces of the body contain sufficient water to allow the pourable liquid vehicle comprising concentrated polyoxyalkylene block copolymers to be effectively delivered to the desired site wherein the accompanying compositions, materials and substances tenaciously adhere to the moistened surfaces and resist dissolution or erosion by water or biological fluid. Such uses include, but are not limited to the delivery of personal health care compositions, formulations and compounds including, but not limited to, pharmaceuticals (OTC and prescription), nutrients and the like.
In the discipline of pharmaceutical compositions there are a wide variety of dosage forms. Examples include tablets, capsules, elixirs, syrups, liquid-filled capsules, suspensions, coated tablets or capsules for administration by mouth; gels, rinses, dentifrices, lozenges, sprays, medicated lollipops, liquid filled capsules for intra-oral administration; gels, suspensions or solutions for intra-ocular or intra-aural administration; suppositories and douches or enemas for intra-rectal or vaginal administration; and creams, ointments, gels, lotions and patches for topical application on the skin and scalp; and liquid suspension or solutions for injection by syringe, nasal gels, solutions, or suspensions for application into the nose with special applications or sprayers.
The majority of these compositions are in the physical form of a fluid having a viscosity ranging from pourable liquids to stiff gels. Pourable liquids are often preferred since they are in the best form to be administered. For example, only liquids, or perhaps low viscosity gels, can be injected through a syringe, or poured from a bottle into a medicine cup, or drawn up into a syringe or medicine dropper, or squeezed from a dropper bottle into the eye or ear, or atomized into the nasal cavities. In addition to the compatibility with pharmaceutical administration devices and with the mode of introduction into the body, it is often desirable for the composition to easily spread after application without the aid of manual action or devices. The eye drop compositions, for example, need to spread over the surface of the eye, as do swallowed liquids intended to coat the throat, esophagus, or stomach. This is similarly true of rectal enemas or vaginal douche compositions.
In many cases, however, pharmaceutical dosage forms in form of pourable liquids are not necessarily desirable since once administered, such pourable liquids are easily removed from the intended treatment site. In such circumstances the therapeutic advantage of the composition may be significantly diminished or even lost completely. It is appropriate, therefore, to surmise that for the purpose of being retained at the targeted site, it may be desirable for a particular pharmaceutical composition to be more viscous, even in the form of a gel that is not readily flowable. It is, however, difficult or even impossible to administer such a viscous composition to its intended site to do the most good. For example, serious injury could occur when attempting to spread a gel on the surface of one""s eye using a finger or more elaborate applicators. More problematic is coating the stomach lining, as this site is simply not accessible using simple self-administer applicators.
There is, therefore, a need for pharmaceutical compositions that are xe2x80x9csmartxe2x80x9d; that is, capable of being administered in a pourable liquid that are converted or transformed after administration into a vehicle having sufficient viscosity to essentially remain at the targeted site. Such compositions require a built-in chemical or physical triggering mechanism(s) that respond to conditions after application in or on a surface including the body.
Attempts to develop such compositions have been ongoing for a significant period of time. Examples of such compositions include intra-ocular dosage forms as disclosed in Edsman, K., Carlfors, J., Petersson, R., Rheological Evaluation of Poloxamer as an In Situ Gel for Ophthalmic Use, European Journal of Pharmaceutics Vol. 6 pp.105-112 (1998) herein incorporated by reference. Compositions such as these are broadly described as primarily aqueous solutions of block co-polymer surfactants, other wise referred to as xe2x80x9cpoloxamersxe2x80x9d, that are commonly known in the art. When formulated in water as somewhat concentrated solutions, or with water and co-solvents, the poloxamer solution remains as a pourable liquid. The most commonly reported example of this type of system consists of poloxamer 407 at concentrations ranging from about 10% to 35% by weight of the composition in water. These compositions are administered at room temperature as liquids. They form a gel upon reaching body temperature. The trigger for converting these compositions to a gel, therefore, is body heat.
In situ gelation of pharmaceutical compositions based on poloxamer that are biologically triggered are known in the art. For example Kim, C. K., Lee, S. W., Choi, H. G., Lee, M. K., Gao, Z. G., Kim, I. S., and Park, K. M.: Trials of In Situ Gelling and Mucoadhesive Acetaminophen Liquid Suppository in Human Subjects, International Journal of Pharmaceutics vol. 174, pp. 201-207 (1998) incorporated herein by reference. Kim et al. discloses liquid suppositories for enhancing absorption of the pain and fever relieving drug acetaminophen.
U.S. Pat. No. 5,256,396, issued Oct. 26, 1993, to Colgate Palmolive Company, incorporated herein by reference, describes similar compositions containing poloxamer 407 and water at specified concentrations. Other products utilizing bio-triggers include those comprising poloxamer 407 at ranges preferably 12% to 17%. When combined with pharmaceutically active agents, these compositions are injected into the gingival space between the root of a tooth and the gum.
Poloxamers represent a large family of polymers that vary in molecular weight as well as in the percentage or portion of the block copolymer that is considered hydrophobic. Compositions comprising other poloxamers from this family having similar liquid/gelling characteristics are somewhat predictable, lacking only in the understanding of the required concentration of poloxamer. While there is a large number of uses for such compositions, they all rely on the same general mechanism of temperature-induced gelation of aqueous poloxamer dispersions. Compositions known in the art are found to be inadequate, however, as the gel structure readily dissolves in aqueous environments.
The present invention covers pourable liquid vehicles used to deliver compositions, materials and substances to moistened surfaces and aqueous environments. The benefits of compositions formulated with such pourable liquid vehicles include retention of the compositions, materials and substances on the moistened surface. This in turn allow for effective delivery of a desired composition, material and substance in the vehicle that acts on targeted surface, resisting erosion or run-off even in an aqueous environment. Such pourable liquid vehicles have a number of utilities for delivery of all kinds of materials including but not limited to cleaning and treating surfaces of objects as well as biological or living organisms, including living creatures.
Another object of this invention is to utilize such pourable liquid vehicles to deliver health care compositions and materials and substances to living creatures, particularly mammals, and most particularly humans. Even another object of the present invention is to develop a method for effective delivery of health care compositions, materials and substances.
Terms useful herein are defined below. Additionally, terms used in the art, as well as general concepts, are further described in Schramm, The Language of Colloid and Interface Science, American Chemical Society, (1993), incorporated herein by reference.
The term xe2x80x9cpourable liquidxe2x80x9d as used herein means the physical state of the compositions of the present invention prior to formation of a gel.
The term xe2x80x9cmoistened surfacexe2x80x9d as used herein means any living or non-living surface having sufficient moisture in or on it to trigger rapid conversion of a pourable liquid to a gel.
The term xe2x80x9cin situ gelationxe2x80x9d as used herein means the conversion of a pourable liquid to a gel at a designated site or surface.
As used herein, the term xe2x80x9cgelxe2x80x9d describes the substance resulting from the combination of the pourable liquid and water, or bodily fluid containing mostly water. The gel is sufficiently viscous to remain at the site applied to, or ultimately targeted for, over a period of time sufficient for the compositions, materials and substances in the gel to bring about a desired result at the site they are delivered to.
The term xe2x80x9ctriggering devicexe2x80x9d as used herein means a stimulus external to the composition that induces the conversion of a pourable liquid to a gel.
The term xe2x80x9cshearxe2x80x9d as used herein is the rate of deformation of a fluid when subjected to a mechanical shearing stress. In simple fluid shear, successive layers of fluid move relative to each other such that the displacement of any one layer is proportional to its distance from a reference layer. The relative displacement of any two layers divided by their distance of separation from each other is termed the xe2x80x9cshearxe2x80x9d or the xe2x80x9cshear strainxe2x80x9d. The rate of change with time of the shear is termed the xe2x80x9cshear ratexe2x80x9d.
A certain applied force is needed to produce deformation in a fluid. For a plane area around some point in the fluid and in the limit of decreasing area the component of deforming forces per unit area that acts parallel to the plane is the xe2x80x9cshear stressxe2x80x9d.
The xe2x80x9cviscosityxe2x80x9d of a viscous material, also called viscosity index, is defined as the ratio of the shear stress applied into the material, divided by the rate of shear which results. Materials of a higher viscosity have a higher resistance to flow, or to forces which can induce flow, than a lower viscosity material. All viscosities listed herein are at a shear rate of about 50 per second unless otherwise indicated. All of the rheologic characteristics given herein can be measured in a controlled rate or a controlled stress rotational viscometer capable of some operation in a controlled rate mode, for Example Haake RS 150 by Haake GmbH, Karlsruhe, Germany; Carrimed CSL 500 Controlled Stress Rheometer by TA Instruments, New Castle, Delaware; and Rheometric SR5, by Rheometric Scientific, Piscataway, N.J.
Specifically, when subject to constant shearing rate of about 50 per second at normal ambient temperature (approx. 25xc2x0 C.), the present liquid compositions have a viscosity of less than about 7 pascal seconds, preferably less than about 2 pascal seconds, more preferably less than about 1 pascal seconds.
The value of a composition""s triggered viscosity ratio (xe2x80x9cTxe2x80x9d) is useful in determining the degree to which a composition exhibits the above described gelling characteristic. The formula and procedure for determining the triggered viscosity ratio is set forth below.
It is desirable for the compositions of the present invention to exhibit a triggered viscosity ratio of at least about 1.3, preferably at least about 2, more preferably at least about 5, and most preferably at least about 10 wherein the triggered viscosity is defined by the following formula or ratio:
T=xcex7g/xcex7f
where xcex7g=viscosity of the gel and
where xcex7f=viscosity of the pourable liquid
The pourable liquid vehicle of the present invention must be selected and formulated so that the contacting and mixing said vehicles to a mucosal surface of the body, or with some other fluid in the body, triggers the conversion of the pourable liquid vehicle to a more viscous gel-like mixture. Examples of these fluids are saliva, gastric fluid, intestinal fluid, extracellular fluid present under the skin at the site of a subcutaneous injection, or in muscle tissue at the site of an intramuscular injection, cerebrospinal fluid, vaginal fluid, fluid exudate from an open wound or ulcer, tear fluid, rectal fluid, or any other bodily fluid of an animal which contains in large measure water. In other words, after the pourable liquid vehicle contacts with the bodily fluid, the viscosity of the pourable liquid vehicle becomes greater than the viscosity of either the pourable liquid vehicle itself prior to mixing, or the bodily fluid alone.
The triggered viscosity ratio of a pourable liquid vehicle can be determined by one skilled in the art using appropriate viscosity measuring instruments, and is exemplified by the following method. First, the viscosity of the pourable liquid vehicle (xcex7f) is determined in a rheometer using a shear rate of 50 per second at 25xc2x0 C. For the determination of xcex7f, 1 ml of the pourable liquid vehicle is placed onto the plate of a Haake RS 150 rheometer. The temperature is controlled in the range of typical room temperature, about 25xc2x0 C. A cover is used on the measuring system and a solvent-saturated atmosphere provided to prevent evaporation of water, ethanol, or other volatile components from the sample during the test. A 35 mm diameter parallel plate measuring system is lowered onto the sample, leaving a gap of about 1 millimeter, and an equilibration shearing of approximately 10 per second is applied for 10 seconds. Then, a constant shearing rate of 50 per second is applied for 30 seconds. The viscosity xcex7f is read from the instrument at the 30 second time point.
For the determination of xcex7g, two dilutions of the pourable liquid vehicle are made with water. The first dilution is made to contain 75% by weight of the pourable liquid vehicle, and 25% by weight of additional water. The second dilution is made to contain 50% by weight of pourable liquid vehicle and 50% by weight of additional water. The pourable liquid vehicle and water are combined in a vial and a tight seal applied to prevent evaporation of components. The vial contents are mixed in an unusual manner, by repeated centrifugation. This is necessary since some of the combinations are very viscous gels. Specifically, the vials are centrifuged (using for example a Beckman GS-6R centrifuge, available from Beckman Instruments, Palo Alto, Calif.) 20 minutes at 3000 RPM and 25xc2x0 C. for at least four separate centrifuge runs. After each run the vials are inverted. Additional runs are conducted in the centrifuge to ensure complete mixing. 1 ml of the gelled sample is then loaded onto the plate of the same rheometer used for the measurement of xcex7f, except that the temperature is controlled at the normal body temperature of a human, 37xc2x0 C. An identical rheometer measurement program is used as for determination of xcex7f. The triggered viscosity factor for both the 25% and 50% dilution of the sample is calculated from xcex7f and xcex7g as described by the formula above. These two dilutions have been found to be useful for measuring the gelling functionality of the pourable liquid vehicles of the invention in a standardize method, because some of the pourable liquid vehicles may require a greater or lesser amount of water in order to trigger the gelling character. The use of other water dilutions for determination of xcex7g, ranging from about 5% up to about 70%, would also be expected to provide a demonstration of the unique, gelling character of the invention, but the dilution which yields a maximal value of T varies depending upon the exact pourable liquid vehicle being tested.
All percentages of the components comprising the invention are herein referred to their weight in the pourable liquid vehicle as a whole.
The present invention is a pourable liquid vehicle comprising:
(a) from about 26% to about 100% polyoxyalkylene block copolymer;
(b) from about 0% to about 70% glycol; and
(c) from about 0% to about 50% water;
wherein said vehicle is used to deliver compositions, materials and substances to moistened surfaces and aqueous environments said vehicle has a viscosity value xcex7f less than or equal to 7 pascal-seconds and the value T greater than or equal to about 1.3.
Polyoxyalkylene block copolymers herein referred to as xe2x80x9cpoloxamersxe2x80x9d are nonionic block copolymers of ethylene oxide and propylene oxide corresponding to the following structure: 
wherein x, y, and xxe2x80x2 have a value wherein the pourable liquid vehicle has a viscosity value nf less than or equal to 7 pascal-seconds and the value T greater than or equal to about 1.3. Preferable polyoxyalkylene block copolymers useful in the present invention include wherein x has a value from about 1 to about 130, y has a value from about 1 to about 72, and xxe2x80x2 has a value from 0 to about 130, wherein the average molecular weight of said copolymer is from about 3000 to about 15,000. More preferred is wherein x equals 37, y equals 58, and xxe2x80x2 equals 37, and the copolymer has an average molecular weight of about 6500. Most preferred is wherein x equals 100, y equals 70, and xxe2x80x2 equals 100, and the copolymer has an average molecular weight of about 12,600.
The poly(oxyethylene) segment is hydrophilic and the poly(oxypropylene) segment is hydrophobic. The level of the poloxamers useful in the present invention ranges from about 26% to about 100%, preferably from about 27.8% to about 95%, more preferably 30% to about 90% by weight of the pourable liquid vehicle. In other words, providing the poloxamer has the critical viscosities above, it can be used itself or when combined with other compositions, materials and substances.
A family of poloxamers are available and vary in the number of blocks, the overall average molecular weight, and in the percentage of the molecule which is hydrophilic. A block refers to a single polyoxyethylene or polyoxypropylene segment. Di-block and tri-block polymers have been described. In the case of tri-block copolymers, the blocks can be arranged in the format of one polyoxypropylene block surrounded by 2 polyoxyethylene blocks, that being the most common poloxamer structure, or alternatively as one polyoxyethylene block surrounded by 2 polyoxypropylene blocks, the latter sometimes referred to as a reverse poloxamer. Poloxamers are available under the trade names of Lutrol, Monolan, or Pluronic. The chemical structure, synthesis, and properties have been described [(poly(ethylene oxide)/poly(propylene oxide)] block copolymer surfactants, Paschalis Alexandridis, Current Opinions in Colloid and Interface Science, Vol 2, pp. 478-489 (1997) herein incorporated by reference.
For applications in the health care area, compositions embodying the present invention utilize a specific group of pharmaceutically acceptable block copolymers or poloxamers. These poloxamers are selected from the group consisting of Pluronic F127, P105, F108 and mixtures thereof, all available from BASF Corp.
In addition to the poloxamers, it is desirable in some of the pourable liquid vehicles of the present invention to combine glycols with the poloxamers for controlling the viscosity of the pourable liquid vehicles, These glycols permit the pourable liquid vehicle to remain pourable while containing very high levels of the poloxamer so that administration is convenient, or so that the composition can readily pass through the bore of a syringe or other dosing apparatus, Additionally, these glycols provide solvent capacity for pharmaceutical actives or other composition components. The level of glycols in the present invention is from 0% to about 70%, preferably from about 10% to about 70% and most preferably from about 7% to about 62% of the pourable liquid vehicle.
Glycols are low molecular weight polyols and are selected from the group consisting of monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose and other sugars, ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol, glycerol and mixtures thereof. Preferred glycols are selected from the group consisting of ethanol, glycerol and propylene glycol, and mixtures thereof. Absolute ethanol is available from Aaper Alcohol and Chemical Co., Shelbyville, Ky.
In addition to the poloxamers, and, or the glycol, it is desirable in some of the pourable liquid vehicles of the present invention to include water. Water is useful at a level from 0% to about 50%, preferably about 1% to about 46%, most preferably from about 2% to about 41% of the pourable liquid vehicle.
Preferred embodiments of the present invention utilizing the combination of poloxamers, polyols and water include the following:
1. from about 26% to about 65% Pluronic F127, from about 22% to about 38% ethanol and from about 8% to about 45% water.
2. from about 52% to about 60% Pluronic F108, from about 20% to about 25% ethanol and from about 17% to about 27% water.
3. from about 25% to about 50% Pluronic P105, from about 45% to about 65% propylene glycol and from about 5% to about 20% water.
4. from about 37% to about 77% Pluronic P105, from about 12% to about 28% ethanol, and from about 10% to about 45% water
5. from about 26% to about 49% Pluronic F127, from about 2% to about 12% ethanol, from about 30% to about 68% propylene glycol, and from about about 7% to about 40% water.
As previously stated, the pourable liquid vehicles of the present invention are useful as delivery vehicles for desired compositions, materials and substances that may be dispersed into them. This could range from compositions, materials and substances that are desired to remain on an applied surface for a period of time to deliver a benefit. Examples include antimicrobials for cleansing surfaces including sinks, toilets and shower tile; to body wounds; oral treatment of gingival and buccal tissues as well as teeth surfaces; agricultural uses including elimination of undesirable plants, animals, viruses, bacteria insects, and the like.
The present invention is particularly useful for the delivery of health care compositions, materials, and substances. These materials can range from dietary compositions to promote nutrition or weight loss to pharmacologically effective amounts of agents selected from the group consisting of antibacterial substances, antihistamines, antitussives, anti-inflammatories, expectorants/mucolytics, mast cell stabilizers, leukotriene antagonists, methylxanthines, antioxidants, steroids, bronchodilators, antivirals, biologics, analgesics, anesthetics, antiarthritics, antiasthmatics, urinary tract disinfectives, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, muscle relaxants, antiprotozoals, and mixtures thereof.
Preferred embodiment of the present invention relates to compositions including pharmaceutically acceptable polyoxyalkylene block copolymer and glycols in combination with a pharmacologically active agent. Suitable classes of agents that can be administered by embodiments of the present invention include:
Antibacterial substances such as xcex2-lactum antibiotics, such as cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides; aminoglycoside antibiotics such as gentamycin, kanaranycin, amikacin, sisomicin and tobramycin; nalidixic acids and analogs such as norfloxacin and the antimicrobial combination of fluoroalanine/pentizidone; nitrofarazones, and mixtures thereof.
Antihistamines, including, Hydroxyzine, Pyrilamine, Phenindamine, Dexchlorpheniramine, Clemastine Diphenhydramine, Azelastine, Acrivastine, Levocarbastine, Mequitazine, Astemizole, Ebastine, Loratadine, Cetirizine, Terfenadine, Promethazine, Dimenhydrinate, Meclizine, Tripelennamine, Carbinoxamine, Cyproheptadine, Azatadine, Brompheniramine, Triprolidine, Cyclizine, Thonzylamine, Pheniramine, and mixtures thereof.
Antitussives, including, Hydrocodone, Noscapine, Benzonatate, Diphenhydramine, Chlophedianol, Clobutinol, Fominoben, Glaucine, Pholcodine, Zipeprol, Hydromorphone, Carbetapentane, Caramiphen, Levopropoxyphene, Codeine, Dextromethorphan, and mixtures thereof.
Antiinflammatories preferably Non-Steroidal Anti-inflammatories (NSAIDS) including, Ketoprofen, Indoprofen, Indomethacin, Sulindac, Diflunisal, Ketorolac, Piroxicam, Meclofenamate, Benzydamine, Carprofen, Diclofenac, Etodolac, Fenbufen, Fenoprofen, Flurbiprofen, Mefenamic, Nabumetone, Phenylbutazone, Pirprofen, Tolmetin, Ibuprofen, Naproxen, Sodium naproxen, Aspirin, and mixtures thereof.
Expectorants/Mucolytics, including, Ambroxol, Bromhexine, Terpin, Guaifenesin, Potassium iodide, N-Acetylcysteine, and mixtures thereof.
Mast Cell Stabilizers, preferably intranasally, or orally administered mast cell stabilizers, including, Cromolyn, Oxatamide, Ketotifen, Lodoxamide, Nedocromil, and mixtures thereof.
Leukotriene Antagonists, including, Zileuton and others.
Methylxanthines, including, Caffeine, Theophylline, Enprofylline, Pentoxifylline, Aminophylline, Dyphylline, and mixtures thereof.
Antioxidants or radical inhibitors, including, Ascorbic acid, Tocopherol, Pycnogenol, and mixtures thereof.
Steroids, preferably intranasally administered steroids, including, Beclomethasone, Fluticasone, Budesonide, Mometasone, Triamcinolone, Dexamethasone, Flunisolide, Prednisone, Hydrocortisone and mixtures thereof.
Bronchodilators, preferably for inhalation, including, Albuterol, Epinephrine, Ephedrine, Metaproterenol, Terbutaline, Isoetharine, Terbutaline, Isoetharine, Pirbuterol, Bitolterol, Fenoterol, Rimeterol, Ipratroprium, and mixtures thereof.
Antivirals, including, Amantadine, Rimantadine, Enviroxime, Nonoxinols, Acyclovir, Alpha-Interferon, Beta-Interferon, and mixtures thereof.
Biologics, including, cytokine and celladhesion molecule inhibitors, ICAM antagonists, interleukin agonists or antagonists, hormones, polypeptides, amino acids, nucleotides, antibodies, and mixtures thereof.
Analgesics such as aspirin, acetaminophen, diflunisal, and mixtures thereof. Anesthetics such as lidocaine, procaine, benzocaine, xylocaine, and mixtures thereof.
Antiarthritics such as phenylbutazone, indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone, probenecid, and mixtures thereof.
Antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine, and mixtures thereof.
Urinary tract disinfectives such as sulfamethoxazole, trimethoprim, nitrofurantoin, norfloxacin, and mixtures thereof.
Anticoagulants such as heparin, bishydroxycoumarin, warfarin, and mixtures thereof.
Anticonvulsants such as diphenylhydantoin, diazepam, and mixtures thereof.
Antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin, and mixtures thereof.
Antidiabetics such as insulin, tolbutamide, tolazamide, acetohexamide, chlorpropamide, and mixtures thereof.
Antineoplastics such as adriamycin, fluorouracil, methotrexate, asparaginase, and mixtures thereof.
Antipsychotics such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trfluoperazine, perphenazine, amitriptyline, triflupromazine, and mixtures thereof.
Antihypertensive such as spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride, reserpine, and mixtures thereof.
Muscle relaxants such as melphalan, dantrolene, cyclobenzaprine, methocarbamol, diazepam, and mixtures thereof.
Antiprotozoals such as chloramphenicol, chloroquine, trimethoprim, sulfamethoxazole, and mixtures thereof.
For treatment of vaginal and urethral conditions requiring antifungal, amoebicidal, trichomonoacidal agents or antiprotozoals, the following agents can be used: polyoxyethylene nonylphenol, alkylaryl sulfonate, oxyquinoline sulfate, miconazole nitrate, sulfanilamide, candicidin, sulfisoxazole, nystatin, clotrimazole, metronidazole and mixtures thereof; antiprotozoals such as chloramphenicol, chloroquine, trimethoprim, sulfamethoxazole and mixtures thereof; antiviral effective compounds such as acyclovir and interferon. Spermicidals can be used such as nonoxynal.